The present invention relates to novel neurotensin antagonists useful as pharmaceutical agents, to methods.for their production, to pharmaceutical compositions which include these compounds and a pharmaceutically acceptable carrier, and to pharmaceutical methods of treatment. The novel compounds of the present invention are central nervous system agents. More particularly, the novel compounds of the present invention are antipsychotic agents for treating psychoses such as schizophrenia and are also useful as agents to treat Parkinson's Disease and gastrointestinal (GI) disorders.
Neurotensin (NT), is an endogenous neuropeptide distributed throughout the central nervous system (CNS) (Uhl G. I. R., et al., Prc. Natl. Acad Sci. USA, 74:4059-4063 (1977)) and gastrointestinal (GI) tract (Carraway R., Kitabgi P., Leeman S. E., J. Biol. Chem., 253:7996 (1978)). While the physiological role of neurotensin is not precisely understood it appears to be a regulatory hormone in several systems both in the periphery as well as the central nervous system.
Neurotensin appears to be involved in the etiology of schizophrenia. In the central nervous system it appears to be a regulator of dopamine neurotransmission (Kalivas P., Brain Research Reviews, 18:75-113 (1993) and references cited therein). Neurotensin has been shown to increase both dopamine metabolism and the content of dopamine in the rat brain (Faggin B. M., et al., J. Pharm. Exp. Ther., 252:817-825 (1990)). Electrophysiological studies have shown that neurotensin increases firing of dopamine neurons (Shi W.X., Bunney B. S., Brain Res., 543:315-321 (1991)). In addition, neurotensin immunoreactive axons form synaptic specializations on dopamine perikarya and dendrites (Woulfe J., Beauder A., Brain Res., 479:402-406 (1989)). Expression of the gene encoding for proneurotensin, the metabolic precursor to neurotensin, appears to be regulated by certain antipsychotic drugs (Merchant K., Dobie D. J., Dorsa D.M., Ann. N.Y. Acad. Sci., 668:54-69 (1992)). Clinical evidence for the involvement of neurotensin in the etiology of schizophrenia is suggested by the elevation of neurotensin levels found in the study of postmortem brain tissue of schizophrenics (Nemeroff C. B., et al., Science, 221:972-975 (1983) and references cited therein).. In addition, neurotensin has been suggested to be involved in the etiology of Parkinson's Disease (Chinaglia, G., et al., Neuroscience, 39:351-360 (1990)).
Neurotensin has also been shown to have effects in the GI tract including inhibition of gastric acid secretion and gastric emptying (Blackburn, A. M., Lancet, 1:987-989 (1980)), as well as pancreatic secretion (Sakamoto, T., et al., Surgery, 96:146-153 (1984)). Thus antagonists at the neurotensin receptor may be expected to have beneficial effects on various GI disorders.
To date, most peptide analogs of neurotensin and NT 8-13 (the minimum active fragment of neurotensin) have acted as agonists. Apparent exceptions to this are D-Trp.sup.11 NT and Tyr(Me).sup.11 NT which have been shown in some assays to have weak antagonist activity (Rioux F.R., et al., Eur. J. Pharmacol., 66:373-379 (1980)). Recently, Asp.sup.13 -NT.sup.8-13 and Asp.sup.12 -NT.sup.8-13 have been shown to antagonize histamine release from isolated mast cells (Miller L.A., Cochrane D. E., Carraway R.E., Feldberg R.S., Agents Actions, 38:1-7 (1993)).
Nonpeptidic neurotensin antagonists have also been described. European Published Patent Application EP-477049-A discloses 3-amido pyrazoles of formula (I) and (I') and their salts with acids or bases, and their enantiomers. ##STR1## or carboxyalkyl; alkoxycarbonylalkyl (alkyl has C.sub.1-4); C.sub.3-6 cycloalkyl; tetrahydronaphthyl; pyridyl; naphthyl; or benzyl substituted by R.sub.1, R'.sub.1, and R".sub.1 ; cinnamyl optionally substituted on the phenyl ring by halogen, OH, or C.sub.1-4 alkoxy; quinolyl or isoquinolyl, optionally substituted by R.sub.1, R.sub.1 ', and R.sub.1 "; 2-benzothiazolyl; quinoxalinyl dione; 1-phthalazinyl; benzothiadiazolyl; or methylene substituted by a 5- or 6-membered heterocyclic group; R.sub.1, R'.sub.1, R".sub.1 =H, halogen, OH, C.sub.1-4 alkyl, C.sub.1-4 alkoxy, CF.sub.3, CF.sub.3 O, NO.sub.2, carboxy, or NH.sub.2 ; RIa =benzyl substituted by R.sub.1, R.sub.1 ', and R.sub.1 "; R =H or C.sub.1-4 alkyl; n =0, 1, 2, or 3; either X =H and X'=H, C.sub.1-6 alkyl, aryl, C.sub.1-4 aminoalkyl, C.sub.1-4 hydroxyalkyl, C.sub.1-4 carboxyalkyl; acetamido (C.sub.1-4) alkyl cysteine, guanidino (C.sub.1-4) alkyl, nitroguanidino (C.sub.1-4) alkyl, C.sub.3-7 cycloalkyl, aralkyl (alkyl has C.sub.1-4, aryl may be substituted by halogen, OH, or C.sub.1-3 alkyl), or hetero(C.sub.1-4)alkyl (heteroaryl is imidazolyl or indolyl optionally substituted by C.sub.1-4 alkyl, OH, or C.sub.1-4 alkoxy); or when n =0, X =H and X' and N--R together form an optionally OH-substituted ring of formula (ii)-(iv) or an indolyl, perhydroindole, or 4,5, 6, 7-tetrahydrothieno[2,3-c]-6-pyridyl ring; ##STR2## m=2-4; t=1 or 2;
or X and X'=independently C.sub.1-4 alkyl, C.sub.3-6 cycloalkyl, or phenyl; or X and X' together form a C.sub.2-12 cycloalkyl optionally substituted by C.sub.1-3 alkyl; or X, X' and the C atom to which they are attached form an adamantyl group (which may be substituted by one or two methyl, or by one OH, C.sub.1-3 alkoxy, or halogen), 1-aza adamantyl, quinuclidinyl, 4-piperidinyl (optionally N-substituted by benzyl), 2,2, 6, 6,-tetramethyl piperidinyl, tetrahydronaphthyl, 4-tetrahydropyranyl, 4-tetrahydrothiopyranyl, 2,3-dihydro-(4H)-4-benzo(thio)pyranyl, a group of formula (a), this group being attached to --NR-- and to --COZ by a C atom of one or other rings; a group of formula (b) this group being attached to --NR-- and to --COZ by a C atom on either of the rings (the rings of groups (a) and (b) optionally being substituted by one or two C.sub.1-4 alkyl groups, and the amino acid not being alpha to W when W is O); 2-bicyclo [2,2, 1]hepten-5-yl; 8-oxa-3-bicyclo[3,2,1]oct-6-en3-yl; or 8-oxa-3-bicyclo(3.2.1)octan-3-yl; ##STR3## n.sub.1 =0 or 1; n'.sub.1 =1 or 2; PA1 n.sub.2 =1; PA1 n.sub.3 =2 or 3; PA1 W=C or O; ##STR4## n.sub.4 =2, 3, or 4; n.sub.5 =2 or 3; PA1 W=C or O; PA1 R.sup.1 is --CO.sub.2 H or ##STR12## R.sup.2, R.sup.3, R.sup.4, R.sup.5, and R.sup.6 are each the same or different and each is hydrogen, lower alkyl, lower alkoxy, or halogen; PA1 or a pharmaceutically acceptable base addition salt thereof.
or X=H and X'=adamantyl (optional substituted as above ), 1-aza-adamantyl or a group of formula (a) or (b), the bond between the rings and the carbon carrying COZ and NR not being alpha to W when W is O; Z=OH, C.sub.1-6 alkoxy, O substituted by a protecting group for carboxylic acids ( e. g., t-butyl or optionally substituted benzyl), amino or an N atom substituted by carboxy-C.sub.1-6 alkyl; provided that if Z is the substituted N atom and if n=0, then when X=H, X' is not (CH.sub.2).sub.x --COQ (x=1 or 2, Q=OH or free or substituted amino); RIV=H, halogen, or C.sub.1-6 alkyl; RV=group of formula (v) naphthyl (optionally substituted by C.sub.1-4 alkyl), pyridyl, or styryl (optionally substituted by C.sub.1-4 alkyl); ##STR5## R.sub.5, R'.sub.5, and R".sub.5 =H, halogen, C.sub.1-4 alkyl, OH, C.sub.1-4 alkoxy, NO.sub.2, CF.sub.3, CF.sub.3 O, CN, NH.sub.2, carboxy, carboxy (C.sub.1-4)alkyl, or Ph; or RIV and RV together form a group (vi) ##STR6## where Ph substitutes the pyrazole group in position 5 and the group (CH.sub.2)i, in which i is 1-3, substitutes the pyrazole in position 4; W.sub.1, W.sub.2, and W.sub.3 =H, halogen, or OH.
Gulley D., et al., Proc. Natl. Acad. Sci USA., 90:65-69 (1993) disclose SR 48692, as a nonpeptide neurotensin receptor antagonist. ##STR7##
Snider R. M., et al., Biorg. Med. Chem. Lett., 1535-1540 (1992) disclose UK-73,093, as a nonpeptide neurotensin receptor antagonist. ##STR8##
A series of substituted quinazolines of the formula ##STR9## are disclosed in U.S. Pat. No. 5,204,354 as neurotensin antagonists useful in the treatment of central nervous system disorders.
The compounds disclosed in the aforementioned references do not disclose or suggest the combination of structural variations of the compounds of the present invention. Thus, we have surprisingly and unexpectedly found the compounds of the present invention are neurotensin antagonists.